Despite significant therapeutic advances over the last 10 years, malaria still causes over 660,000 deaths annually. The Plasmodium parasites that cause malaria invade erythrocytes within which they mature as they digest hemoglobin. The proliferation of blood-stage parasites leads to an illness characterized by fever, hemolysis resulting in severe anemia and, in some cases, the neurologic and metabolic complications of cerebral malaria. As resistance to known antimalarial agents spreads, efforts to identify critical new targets to aid the development of novel antimalarial agents grow in importance.
Intracellular ion homeostasis of erythrocytes is important to the pathogenesis of sickle cell disease (SCD) and of malaria. The Gardos channel (KCNN4/IK-1) is a calcium-activated potassium channel expressed in a variety of tissues including hematopoietic tissues, lung, and colon. It is inactive in normal, resting erythrocytes, but is abnormally activated in sickle erythrocytes. Senicapoc, a Gardos channel inhibitor, prevents erythrocyte dehydration in SCD. It has effectively reduced disease severity in murine models of SCD and improved anemia in early phase clinical trials in patients with SCD. Administration of senicapoc to patients with SCD was well tolerated and reduced hemolysis through attenuation of sickle red cell dehydration, but failed to reduce the frequency of vaso-occlusive pain crises (Ataga K I et al. Br J Haematol 2011; 153:92-104).
Red cell volume regulation is critical both to the pathology of sickle cell disease and to the growth of Plasmodium, the parasites that cause malaria, since Plasmodium depends upon ion flow across the host membrane for growth (Glushakova S et al. Curr Biol 2010; 20:1117-1121). Cellular volume regulation also modulates the host defense against malaria infection. The process of intra-erythrocyte parasite maturation and eventual erythrocyte rupture synchronizes parasite swelling with erythrocyte potassium loss and sodium gain, leading to host cell rupture. As parasites mature, parasite-derived ion and nutrient channels insert into the host erythrocyte membrane, facilitating continued growth of the parasite. Parasite growth is impaired in dense, dehydrated sickle erythrocytes.